The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells
The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells
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DOI：
10.1016/j.cell.2006.07.035
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发表时间：
2006-09-22
期刊：
影响因子：
64.5
通讯作者：
Littman, Dan R.
中科院分区：
文献类型：
--
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
IL-17产生T淋巴细胞最近已被证明包含促炎性T辅助细胞的独特谱系，称为Th 17细胞，其是自身免疫性疾病的主要贡献者。我们在这里表明，孤儿核受体ROR γ t是关键的转录因子，协调这种效应细胞谱系的分化。ROR γ t诱导初始CD 4（+）T辅助细胞中编码IL-17和相关细胞因子IL-17 F的基因的转录，并且是它们响应IL-6和TGF-β（已知诱导IL-17的细胞因子）表达所需的。Th 17细胞组成性地存在于整个肠固有层中，表达ROR γ t，并且在ROR γ t或IL-6缺陷的小鼠中不存在。具有ROR γ t缺陷型T细胞的小鼠具有减弱的自身免疫性疾病并且缺乏组织浸润性Th 17细胞。总之，这些研究表明，ROR γ t是免疫稳态的关键调节因子，并突出了其作为炎性疾病治疗靶点的潜力。
IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease. We show here that the orphan nuclear receptor ROR gamma t is the key transcription factor that orchestrates the differentiation of this effector cell lineage. ROR gamma t induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naive CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Th17 cells are constitutively present throughout the intestinal lamina propria, express ROR gamma t, and are absent in mice deficient for ROR gamma t or IL-6. Mice with ROR gamma t-deficient T cells have attenuated autoimmune disease and lack tissue-infiltrating Th17 cells. Together, these studies suggest that ROR gamma t is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases.